Dietary carotenoids provide health benefits by reducing the risk of several chronic disorders. Some of the carotenoids found in the human serum and organs include, for example, β-carotene, lycopene, lutein, and zeaxanthin. The provitamin A activity of β-carotene is well documented. All trans-lutein and all trans-zeaxanthin are the predominant carotenoids found in the human macular pigment. Recent studies have demonstrated a direct relationship between the macular pigment density and age related macular degeneration. Epidemiological and experimental studies have indicated that these carotenoids may prevent age related macular degeneration and other blinding disorders. Lycopene, one of the major carotenoids in the human serum and organs, is reported to reduce the risk of certain types of cancers, such as prostate cancer, digestive tract cancers, and lung cancer. Lycopene also has been reported to be protective against cardiovascular diseases.
Consequently, many dietary supplements, containing isolated carotenoids in their free or esterified forms or mixtures of carotenoids in oil dispersions or as microencapsulated beadlets, now are commercially available. Being lipophilic molecules insoluble in water, the absorption of carotenoids depends on a variety of factors such as, for example, dietary fats, digestive process, and extent of micellarization.
In human studies, both free and esterified forms of lutein showed large variations in absorption (Bowen, P. E., Herbst-Espinosa, S. M., Hussain, E. A., and Stacewicz-Sapuntzakis, M., “Esterification does not impair lutein bioavailability in humans”, J. Nutr., 132: 3668-3673, 2002). Zeaxanthin, the stereoisomer of lutein, was less well absorbed than an equal lutein dose in a human study (Bone, R. A., Landrum, J. T., Guerrs, L. H., and Ruiz, C. A., “Lutein and zeaxanthin supplements raise macular pigment density and serum concentrations in humans”, J. Nutr., 133: 992-998, 2003). High inter-individual variability in lycopene absorption has been reported in human studies (Diwadkar-Navsariwala, V., Novotny, J. A., Gustin, D. M., Sosman, J. A., Rodvold, K. A., Crowell, J. A., Stacewicz-Sapuntzakis, and M., Bowen, P. E., “A physiological pharmacokinetic model describing the disposition of lycopene in healthy men”, J. Lipid Res., 44: 1927-1939, 2003). Improving the uptake of carotenoids, thus, is of interest to the nutritional supplement and pharmaceutical industry.
Cyclodextrins are cyclic oligosaccharides composed of 6, 7, or 8 α-(1-4)-linked anhydroglucose units with a hydrophobic cavity suitable for inclusion of various lipophilic compounds. The α-, β-, and γ-cyclodextrins prepared from starch are considered natural and are GRAS according to the USFDA. Various substituted derivatives, such as, for example, methyl- and hydroxypropyl-cyclodextrins also have been developed to improve the solubility and complexation properties of cyclodextrins. The cyclodextrins are widely used in the pharmaceutical industry to improve the dissolution, sustained release, and uptake of lipophilic compounds.
It is well known in the art that complexation with different cyclodextrins results in products with varying properties. For example, dimethyl β-cyclodextrin was reported to dramatically enhance the absorption of insulin, while hydroxypropyl β-cyclodextrin had no significant effect (Shao, Z., Li, Y., Chermak, T., and Mitra, A. K, “Cyclodextrins as mucosal absorption promoters of insulin. II. Effects of beta-cyclodextrin derivatives on alpha-chymotryptic degradation and enteral absorption of insulin in rats”, Pharm Res., 11:1174-1179, 1994).
The differences in the cavity size of cyclodextrins (α-<β-<γ-) provide some selectivity for complexation with guest molecules. Small molecules with four or fewer carbon atoms form better complexes with α-cyclodextrin, while larger molecules bind best with γ-cyclodextrin. Based on the solubility profile of the natural cyclodextrins, complexes with β-cyclodextrin generally are less soluble as compared to the γ-cyclodextrin complexes. Cyclodextrins also may exhibit stereoselectivity with a mixture of enantiomers resulting in differences in the stability of the complexes formed between each enantiomer and the cyclodextrin and differences in the rate of dissolution and release properties from the complexes.
It is also known in the art that the excipients used in formulations, such as, for example, surfactants, oils, waxes, and phospholipids, may interact with cyclodextrin. This interaction may result in the dissociation of the complex, inhibit the release of the actives (e.g., active ingredients or components), or modulate the dissolution properties (Veiga, M. D. and Ahsan, F., “Influence of surfactants (present in the dissolution media) on the release behavior of tolbutamide from its inclusion complex with beta-cyclodextrin”, Eur. J. Pharm. Sci., 9: 291-299, 2000; Ahsan, F., Arnold, J. J., Meezan, E., and Pillioin, D. J., “Mutual inhibition of insulin absorption-enhancing properties of dodecylmaltoside and dimethyl-beta-cyclodextrin following nasal administration”, Pharm. Res., 18; 608-614, 2001; Shalko-Basnet, N., Pavelic, Z., and Becirevic-Lacan, M., “Liposomes containing drug and cyclodextrin prepared by the one-step spray-drying method”, Drug Dev. Ind. Pharm., 26: 1279-84, 2000).
Complexation of carotenoids, such as, for example, β-carotene and lycopene, with α- and β-cyclodextrins, for example, has been tried by a few investigators as a means to improve their dissolution properties and stability to light and heat (U.S. Pat. Nos. 5,834,445 and 5,221,735). The complexed products are targeted for functional foods and beverages, or for topical applications.
U.S. patent application Ser. No. 10/309,999 describes a process for complexation of lutein with γ-cyclodextrin followed by spray drying as the preferred method of drying. The application has certain drawbacks. Since lutein is not fully protected by complexation, the process may result in reduced product recovery and loss of lutein concentration as a result of exposure to temperature and humidity during the drying and collection of finished product. The application does not explore complexation of lutein with other cyclodextrins or of other carotenoids with cyclodextrins. The application also does not address formulation of the lutein-cyclodextrin complex for incorporation into soft gelatin capsules or other suitable methods of delivery.